Pyruvate limits zinc‐induced rat oligodendrocyte progenitor cell death

Eve E. Kelland; Mary D. Kelly; Nick J. Toms

doi:10.1111/j.0953-816x.2003.03134.x

Pyruvate limits zinc‐induced rat oligodendrocyte progenitor cell death

Eve E. Kelland, Mary D. Kelly, Nick J. Toms^*

^*Corresponding author for this work

University of Surrey

Research output: Contribution to journal › Article › peer-review

Abstract

AbstractA growing body of evidence suggests that excessive Zn2+ release plays a key role in inducing neuronal death during central nervous system injury. However, the possible cytotoxicity of extracellular Zn2+ to oligodendrocyte lineage cells remains unknown. Employing cultures of rat oligodendrocyte progenitor cells (OPC), we report here that OPC are vulnerable to increased extracellular Zn2+ levels and that pyruvate limits Zn2+‐induced OPC death. Zn2+‐induced concentration‐dependent (pEC50 = −4.1 ± 0.1) OPC death, which was insensitive to both α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (Evans Blue) and l‐type Ca2+ channel (nicardipine) inhibition. Neither kainate nor nicardipine influenced OPC 65Zn2+ accumulation, in contrast with the Zn2+ ionophore, pyrithione. Cytotoxic extracellular Zn2+ concentrations failed to increase OPC reactive oxygen species production and the antioxidant reagents, trolox, N,N′‐diphenyl‐1,4‐phenylenediamine and N‐tert‐butyl‐α‐phenylnitrone did not afford significant protection from Zn2+ insults. The apoptotic inducer staurosporine induced the appearance of known apoptotic markers [pyknotic nuclei and caspase‐3 specific (120 kDa) α‐fodrin cleavage fragment], events not reproduced with Zn2+ insults. Zn2+ insults were also insensitive to the pan‐caspase inhibitor Z‐VAD‐fmk. However, pyruvate afforded significant OPC protection from lethal Zn2+ insults. We conclude that cultured OPC are vulnerable to Zn2+ insults, via a nonoxidative stress and noncaspase‐3‐based mechanism, involving Zn2+ inhibition of OPC glycolysis.

Original language	English
Pages (from-to)	287-294
Number of pages	0
Journal	European Journal of Neuroscience
Volume	19
Issue number	2
DOIs	https://doi.org/10.1111/j.0953-816x.2003.03134.x
Publication status	Published - Jan 2004

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@article{3346bb190c0747b28f6c3f1f4786e7c3,

title = "Pyruvate limits zinc‐induced rat oligodendrocyte progenitor cell death",

abstract = "AbstractA growing body of evidence suggests that excessive Zn2+ release plays a key role in inducing neuronal death during central nervous system injury. However, the possible cytotoxicity of extracellular Zn2+ to oligodendrocyte lineage cells remains unknown. Employing cultures of rat oligodendrocyte progenitor cells (OPC), we report here that OPC are vulnerable to increased extracellular Zn2+ levels and that pyruvate limits Zn2+‐induced OPC death. Zn2+‐induced concentration‐dependent (pEC50 = −4.1 ± 0.1) OPC death, which was insensitive to both α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (Evans Blue) and l‐type Ca2+ channel (nicardipine) inhibition. Neither kainate nor nicardipine influenced OPC 65Zn2+ accumulation, in contrast with the Zn2+ ionophore, pyrithione. Cytotoxic extracellular Zn2+ concentrations failed to increase OPC reactive oxygen species production and the antioxidant reagents, trolox, N,N′‐diphenyl‐1,4‐phenylenediamine and N‐tert‐butyl‐α‐phenylnitrone did not afford significant protection from Zn2+ insults. The apoptotic inducer staurosporine induced the appearance of known apoptotic markers [pyknotic nuclei and caspase‐3 specific (120 kDa) α‐fodrin cleavage fragment], events not reproduced with Zn2+ insults. Zn2+ insults were also insensitive to the pan‐caspase inhibitor Z‐VAD‐fmk. However, pyruvate afforded significant OPC protection from lethal Zn2+ insults. We conclude that cultured OPC are vulnerable to Zn2+ insults, via a nonoxidative stress and noncaspase‐3‐based mechanism, involving Zn2+ inhibition of OPC glycolysis.",

author = "Kelland, {Eve E.} and Kelly, {Mary D.} and Toms, {Nick J.}",

year = "2004",

month = jan,

doi = "10.1111/j.0953-816x.2003.03134.x",

language = "English",

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TY - JOUR

T1 - Pyruvate limits zinc‐induced rat oligodendrocyte progenitor cell death

AU - Kelland, Eve E.

AU - Kelly, Mary D.

AU - Toms, Nick J.

PY - 2004/1

Y1 - 2004/1

N2 - AbstractA growing body of evidence suggests that excessive Zn2+ release plays a key role in inducing neuronal death during central nervous system injury. However, the possible cytotoxicity of extracellular Zn2+ to oligodendrocyte lineage cells remains unknown. Employing cultures of rat oligodendrocyte progenitor cells (OPC), we report here that OPC are vulnerable to increased extracellular Zn2+ levels and that pyruvate limits Zn2+‐induced OPC death. Zn2+‐induced concentration‐dependent (pEC50 = −4.1 ± 0.1) OPC death, which was insensitive to both α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (Evans Blue) and l‐type Ca2+ channel (nicardipine) inhibition. Neither kainate nor nicardipine influenced OPC 65Zn2+ accumulation, in contrast with the Zn2+ ionophore, pyrithione. Cytotoxic extracellular Zn2+ concentrations failed to increase OPC reactive oxygen species production and the antioxidant reagents, trolox, N,N′‐diphenyl‐1,4‐phenylenediamine and N‐tert‐butyl‐α‐phenylnitrone did not afford significant protection from Zn2+ insults. The apoptotic inducer staurosporine induced the appearance of known apoptotic markers [pyknotic nuclei and caspase‐3 specific (120 kDa) α‐fodrin cleavage fragment], events not reproduced with Zn2+ insults. Zn2+ insults were also insensitive to the pan‐caspase inhibitor Z‐VAD‐fmk. However, pyruvate afforded significant OPC protection from lethal Zn2+ insults. We conclude that cultured OPC are vulnerable to Zn2+ insults, via a nonoxidative stress and noncaspase‐3‐based mechanism, involving Zn2+ inhibition of OPC glycolysis.

AB - AbstractA growing body of evidence suggests that excessive Zn2+ release plays a key role in inducing neuronal death during central nervous system injury. However, the possible cytotoxicity of extracellular Zn2+ to oligodendrocyte lineage cells remains unknown. Employing cultures of rat oligodendrocyte progenitor cells (OPC), we report here that OPC are vulnerable to increased extracellular Zn2+ levels and that pyruvate limits Zn2+‐induced OPC death. Zn2+‐induced concentration‐dependent (pEC50 = −4.1 ± 0.1) OPC death, which was insensitive to both α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (Evans Blue) and l‐type Ca2+ channel (nicardipine) inhibition. Neither kainate nor nicardipine influenced OPC 65Zn2+ accumulation, in contrast with the Zn2+ ionophore, pyrithione. Cytotoxic extracellular Zn2+ concentrations failed to increase OPC reactive oxygen species production and the antioxidant reagents, trolox, N,N′‐diphenyl‐1,4‐phenylenediamine and N‐tert‐butyl‐α‐phenylnitrone did not afford significant protection from Zn2+ insults. The apoptotic inducer staurosporine induced the appearance of known apoptotic markers [pyknotic nuclei and caspase‐3 specific (120 kDa) α‐fodrin cleavage fragment], events not reproduced with Zn2+ insults. Zn2+ insults were also insensitive to the pan‐caspase inhibitor Z‐VAD‐fmk. However, pyruvate afforded significant OPC protection from lethal Zn2+ insults. We conclude that cultured OPC are vulnerable to Zn2+ insults, via a nonoxidative stress and noncaspase‐3‐based mechanism, involving Zn2+ inhibition of OPC glycolysis.

U2 - 10.1111/j.0953-816x.2003.03134.x

DO - 10.1111/j.0953-816x.2003.03134.x

M3 - Article

SN - 0953-816X

VL - 19

SP - 287

EP - 294

JO - European Journal of Neuroscience

JF - European Journal of Neuroscience

IS - 2

ER -

Pyruvate limits zinc‐induced rat oligodendrocyte progenitor cell death

Abstract

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